InteractionsGuide Index Page

Androgen-Deprivation Therapy

Effect and Mechanism of Action

The uric acid–lowering agent allopurinol may elevate serum concentrations of 1,25-dihydroxycholecalciferol, the active form of vitamin D. Uric acid may directly decrease the serum concentration of 1,25(OH) ² -vitamin D ³ in patients with gout by inhibiting 1-hydroxylase activity.

Research

Takahashi et al. ⁴⁵ measured the serum concentrations of 1,25(OH) ² -vitamin D ³ , 25(OH)-vitamin D ³ , and parathyroid hormone (PTH) in 82 male patients with primary gout whose serum uric acid was significantly higher than that of 41 normal control male subjects. The patients with gout exhibited a significantly decreased serum concentration of 1,25(OH) ² -vitamin D ³ , which was corrected as uric acid levels dropped. These researchers reported that administration of allopurinol for 1 year caused a significant increase in their serum 1,25(OH) ² -vitamin D ³ concentration (along with a significant decrease in their serum uric acid concentration). Notably, the serum concentrations of 25(OH)-vitamin D ³ and PTH were not affected.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Individuals diagnosed with gout may have compromised vitamin D status and should be assessed for vitamin D deficiency. Coadministration of a uric acid–lowering agent such as allopurinol may elevate 1,25(OH) ² -vitamin D ³ levels. Supplementation with vitamin D (5-10 µg/day) may be advisable and is unlikely to present any significant risk, particularly under reasonable supervision and regular monitoring.

Antiandrogens: Bicalutamide (Casodex), cyproterone (Androcur, Cyprostat, Cyproteron, Cyprone, Cyprohexal, Ciproterona, Cyproteronum, Neoproxil, Procur, Siterone), flutamide (Chimax, Drogenil, Euflex, Eulexin), nilutamide (Anandron, Nilandron). Gonadotropin-releasing hormone (GnRH) agonists/analogs: Goserelin (Zoladex), leuprolide (Eligard, Lupron, Lupron Depot, Viadur), triptorelin (De-capeptyl Trelstar, Trelstar LA).

	Prevention and Reduction of Drug Adverse Effect
	Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Anticonvulsant Medications, Including Phenobarbital, Phenytoin, and Valproic Acid

Effect and Mechanism of Action

Decreased levels of sex hormones are generally associated with increased risk of diminished bone mineral density (BMD) and osteoporosis. Supplementation of vitamin D can optimize and preserve bone mass, which tends to be adversely affected by androgen-deprivation therapy (ADT) and is associated with increased risk of osteoporosis and fractures.

Research

Research directly investigating prevention and treatment of osteoporosis caused by ADT is limited. Normally, the incidence of osteoporotic fractures usually increases a decade later in men than in women. Osteoporosis in men with gonadal steroid deficiency can derive from a variety of causes. Gonadotropin-releasing hormone agonists (which, after causing an initial surge in testosterone, result in castrate levels that are maintained as long as the drug is administered) hasten this process and increase bone loss, increasing the risk of osteoporosis and fractures, which have been widely documented in men prescribed ADT for the treatment of prostate carcinoma. ^46-53 Four retrospective studies have shown a significant association between ADT and elevated fracture risk in men with prostate cancer. ^48,54-56 In particular, with GnRH agonists, men with fractures had lower BMD and higher biochemical markers of bone resorption than men without fractures. ⁵⁵ Collectively, the available studies indicate that the first year of ADT results in a 5% to 10% decrease in BMD in men with prostate cancer, an effect greater than that associated with menopause. ⁵⁷ Furthermore, in a cross-sectional study of hormone-naive men with prostate cancer, Smith et al. ⁵⁸ observed vitamin D deficiency and inadequate dietary intake of calcium in 17% and 59%, respectively.

Smith et al. ⁵⁹ also found that concurrent treatment with calcium, vitamin D, and pamidronate (a bisphosphonate drug) during ADT increases serum concentrations of both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. Bisphosphonates have come to play an important role in supporting bone mass. ^59-62 Coadministration of vitamin D (and calcium), particularly with bisphosphonates, is generally accepted. ⁵¹ The rationale and supporting research are further discussed in the Bisphosphonates section.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

As with postmenopausal women and HRT, concomitant calcium and vitamin D enable and enhance the fundamental preventive support provided by diet and regular weight-bearing exercise in maintaining (or restoring) bone health, particularly bone mass and BMD. Smoking cessation, moderate alcohol consumption, and other supportive lifestyle modification should be also encouraged. The administration of bisphosphonates constitutes a further intervention as part of conventional care. Clinical management should evolve in response to the results of urinary assessment of bone breakdown (e.g., deoxypyridinium metabolites) and radiographic, DXA (dual-energy x-ray absorptiometry), ultrasound, or other techniques for BMD assessment. Oral intake of the bisphosphonate and calcium should be separated by at least 2 hours.

Evidence: Divalproex semisodium, divalproex sodium (Depakote), gabapentin (Neurontin), phenobarbital (phenobarbitone; Luminal, Solfoton), phenytoin (diphenylhydantoin; Dilantin, Phenytek), sodium valproate (Depacon), valproate semisodium, valproic acid (Depakene, Depakene Syrup). Extrapolated, based on similar properties: Carbamazepine (Carbatrol, Tegretol), clonazepam (Klonopin), clorazepate (Tranxene), diazepam (Valium), ethosuximide (Zarontin), ethotoin (Peganone), felbamate (Felbatol), fosphenytoin (Cerebyx, Mesantoin), lamotrigine (Lamictal), levetiracetam (Keppra), mephenytoin, mephobarbital (Mebaral), methsuximide (Celontin), oxcarbazepine (GP 47680, oxycarbamazepine; Trileptal), piracetam (Nootropyl), primidone (Mysoline), topiramate (Topamax), trimethadione (Tridione), vigabatrin (Sabril), zonisamide (Zonegran).

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern
	Prevention or Reduction of Drug Adverse Effect

Probability: 2. Probable
Evidence Base:

Calcitriol and Vitamin D Analogs

Effect and Mechanism of Action

Phenobarbital and related anticonvulsants are inducers of cytochrome P450 and the mixed-function oxidase system. Phenobarbital impairs bioavailability of vitamin D. Phenytoin and phenobarbital may reduce serum levels of 25(OH)D (calcidiol) by altering hepatic metabolism of vitamin D, at least in part by accelerating its metabolism. ^{63, 64} Antiepileptic drugs (AEDs) that induce the enzyme CYP3A4 are of particular concern because 3A4 degrades vitamin D, which can create effects consistent with secondary hyperparathyroidism; AEDs that induce 3A4 include phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and felbamate. Vitamin D therapy does not appear to alter serum phenytoin levels, but phenytoin may limit the ability of some individuals to respond to vitamin D therapy or may require larger doses of vitamin D to maintain optimal blood levels of 25-OHD. Thus, anticonvulsants impair mineralization, leading to increased risk of osteomalacia and osteoporosis.

High-dose vitamin D therapy can significantly counter vitamin D depletion and improve BMD and prevent bone loss associated with anticonvulsant treatment.

Research

Long-term therapy with phenytoin and other anticonvulsants can disturb vitamin D and calcium metabolism and result in osteomalacia. Both epilepsy and anticonvulsant medications are independent risk factors for low BMD, regardless of vitamin D levels. Long-term anticonvulsant treatment can cause excessive metabolism and deficiency of vitamin D and is believed to be associated with decreased BMD and bone loss.

In a 1982 study of 30 adult epileptic patients, Zerwekh et al. ⁶⁵ reported decreased serum 24,25-dihydroxyvitamin D concentration during long-term anticonvulsant therapy (with phenytoin, phenobarbital, or carbamazepine), with phenobarbital-treated patients exhibiting a significant decrease in serum 25(OH)D. They noted that various anticonvulsant agents appear to exert different effects on vitamin D metabolism.

After finding no pattern of low serum levels of vitamin D (25[OH]D) or radiological evidence of osteomalacia or rickets in more than 400 individuals using anticonvulsants in Florida, Williams et al. ⁶⁶ concluded that the climate provided adequate exposure to sunshine and thereby prevented the development of anticonvulsant-induced osteomalacia or rickets. “In contrast to reports from northern climates, we found minimal evidence of anticonvulsant-induced bone disease.” Subsequently, in a controlled trial, Riancho et al. ⁶⁷ studied 17 ambulatory epileptic children taking anticonvulsants for two seasons with high and low levels of solar radiation and observed that although serum 25-OHD concentrations were normal among medicated subjects during the summer, their levels were significantly lower than those of controls during the winter months.

In initiating a prospective 3-year study, Hunt et al. ⁶⁸ found that, of 144 children and young adults who required anticonvulsant therapy, 52 were found to have serum alkaline phosphatase (ALP) levels elevated more than two standard deviations (SDs) above normal, and half of these showed signs of rickets or osteomalacia. After slow and gradual but varying rates of response to calcitriol, all patients showed significant lowering of serum ALP levels by 30 months of follow-up. In a later controlled study, Jekovec-Vrhovsek et al. ⁶⁹ determined that bone strength improved (specifically, BMD increased) in 13 institutionalized children under long-term anticonvulsant therapy who were supplemented for 9 months with 0.25 µg daily 1,25-dihydroxycholecalciferol vitamin D, the activated form of vitamin D, and 500 mg daily calcium. ⁶⁹

Telci et al. ⁷⁰ compared bone turnover in 52 epileptic patients receiving chronic anticonvulsant therapy with 39 healthy volunteers as matched controls and found that the resorption phase of bone turnover is affected during chronic anticonvulsant therapy. Total serum ALP levels (a marker of bone formation) were significantly increased in patients from both genders compared with those of controls. Among male epileptic patients, urinary deoxypyridinoline levels (a marker of bone resorption) were significantly increased and 25-OHD levels significantly reduced compared with controls. ⁷⁰

Farhat et al. ⁷¹ compared the effects of various AEDs on bone density in 71 adults and children over at least 6 months. More than half the adults and children/adolescents had low serum 25-OHD levels. Although this finding did not correlate with their BMD, AEDs were strongly associated with decreased BMD in the adults, particularly at skeletal sites enriched in cortical bone. Furthermore, lower BMD was more consistently associated with enzyme-inducing agents (e.g., phenytoin, phenobarbital, carbamazepine, primidone) than with medications that did not induce enzymes (e.g., valproic acid, lamotrigine, clonazepam, gabapentin, topamirate, ethosuximide). These researchers concluded: “Generalised seizures, duration of epilepsy, and polypharmacy were significant determinants of bone mineral density.” ⁷¹

Although it has been generally established that certain AEDs constituted a risk factor for osteoporosis and fractures in postmenopausal women, data regarding men have largely been lacking. In findings presented at the First North American Regional Epilepsy Congress, Jetter et al. ⁷² found that “enzyme-inducing AEDs do significantly affect vitamin D, calcium, and parathyroid hormone levels.” In this study, researchers focused on phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and felbamate as enzyme 3A4–inducing AEDs. Because 3A4 degrades vitamin D, they set out to determine whether levels of 25-hydroxyvitamin D ³ (25-OH-D ³ ), PTH, or calcium differed between men taking 3A4 enzyme–inducing AEDs and those taking other types of AEDs. The researchers obtained 25-OH-D ³ , intact PTH, and calcium levels in 210 male veterans, age 20 to 89 (average, 58), who had been treated with AEDs for an average of 20.3 years. On analysis, they found that the 126 patients treated with at least one enzyme-inducing AED for at least the past 6 months exhibited an average 25-OH-D ³ level of 19.2 ng/mL, compared with 23.8 ng/mL in those taking non–enzyme-inducing AEDs ( p=.005). The patients taking enzyme-inducing AEDs had a blood calcium level of 8.83 mg/dL, whereas the 64 treated with only non–enzyme-inducing AEDs for that period exhibited levels of 9.16 mg/dL ( p=.00009). The intact PTH levels averaged 52.5 pg/mL for patients on enzyme-inducing AEDs and 38.2 pg/mL for patients on non–enzyme-inducing AEDs ( p=.0002). The 20 patients treated with divalproex sodium were analyzed separately. The authors concluded that the “findings suggest that a secondary hyperparathyroidism is associated with the use of these drugs and that dietary supplementation of vitamin D may be necessary to prevent osteoporosis.” Furthermore, the investigators emphasized that neurologists need to monitor BMD in men treated with these medications, parallel to recommendations regarding female patients. ⁷²

In 2001, Valmadrid et al. ⁷³ published a survey of practice patterns of neurologists. They found that only 41% of pediatric and 28% of adult neurologists performed routine evaluation of patients taking AEDs for either bone or mineral disease. Further, among those physicians who detected bone disease through such diagnostic testing, 40% of pediatric and 37% of adult neurologists prescribed either calcium or vitamin D. However, only 9% of pediatric and 7% of adult neurologists prescribed prophylactic calcium or vitamin D for patients receiving AED therapy.

In two parallel, randomized, controlled trials involving 72 adults (18-54 years old) and 78 children and adolescents (10-18 years), Mikati, Fuleihan, et al. ⁷⁴ investigated the effects of two doses of vitamin D given over 1 year on BMD in ambulatory patients on long-term AED therapy. Adult subjects received either “low-dose vitamin D” (400 IU/day) or “high-dose vitamin D” (4000 IU/day), and children and adolescents received 400 or 2000 IU/day. At baseline, 34% of the adults were in the deficient range of vitamin D levels, and 46% were in the insufficient range; the parallel levels for children were 18% and 44%, respectively. Likewise, using DXA, baseline BMD in adults was lower than that of age-matched and gender-matched controls versus either a Western or an ethnically identical population. After treatment, none of the adults and only a few of the children in the high-dose group still exhibited vitamin D deficiency, and relatively few had vitamin D insufficiency. Furthermore, the authors demonstrated that “significant increases in BMD at all skeletal sites compared to baseline” after 1 year in the high-dose, but not in the low-dose, vitamin D group. Nevertheless, BMD at 1 year remained below normal. Notably, baseline BMD was normal in children (compared with age- and gender-matched controls), and both treatment groups “showed significant and comparable increases” in BMD. The authors concluded that in “ambulatory adults on antiepileptic drugs, high-dose vitamin D therapy substantially increased bone mineral density at several skeletal sites,” and that “both doses resulted in comparable increases in bone mass” in children. These findings represent the first clinical trials demonstrating that high-dose vitamin D therapy significantly improves BMD in patients receiving AED therapy. ⁷⁴

Report

Duus ⁷⁵ reported a case of several severe fractures in a patient following epileptic seizures. The patient had epileptic osteomalacia and responded well to vitamin D treatment.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Many individuals with epilepsy, especially children, lead restricted lifestyles and are often institutionalized or under other forms of full-time care. Such individuals not only experience the effects of the pathophysiology on vitamin D metabolism, but also tend to have compromised nutritional status and restricted time outdoors in the sun, especially during winter months. Thus, sunlight represents an effective and low-risk method of supporting vitamin D status. Oral supplementation can also be recommended. A moderate dose of 400 to 1500 IU/day of vitamin D could exert a protective function for individuals using phenobarbital or phenytoin who are concerned about potential drug-induced rickets, osteomalacia, or osteoporosis. Pretreatment and posttreatment monitoring of serum 25-OHD and 1,25-(OH) ² D levels would also identify individuals at risk of treatment-induced and nutritional/sunlight-related deficiencies of vitamin D. Available evidence indicates that such supplementation does not represent a significant risk of interfering with the therapeutic activity of standard anticonvulsant agents. However, as previously suggested, regular exposure to sunlight represents an effective and low-risk method of supporting vitamin D status by providing adequate stimulation of endogenous synthesis of necessary levels of vitamin D. Others have advocated a proactive approach toward the risks of bone loss while voicing caution that given the increased risk of osteomalacia, osteoporosis, and rickets among those taking anticonvulsants, withdrawal from such drugs carries potential for increased risk of seizure-related fractures. Monitoring of bone status is often appropriate.

Bisphosphonates

Effect and Mechanism of Action

The ability of bisphosphonates to inhibit osteoclastic activity and bone resorption, maintain healthy bone mineralization, and produce substantial gains in bone mass depends on the presence of adequate vitamin D and other nutrients (e.g., protein, calcium, phosphorus). ^76,77 Calcium, the principal element in bone, can be absorbed in the brush border of the intestinal mucosa only when vitamin D is present. Notably, bisphosphonates have been used effectively to treat the more resistant cases of vitamin D–induced hypercalcemia.

Research

All currently approved, bone-active pharmacological agents have been studied only in conjunction with supplemental calcium, and newer anabolic agents increase mineral demand in skeletal tissue and will thus require even higher levels of calcium repletion. ⁷⁸ The consensus underlying the fundamental importance of vitamin D and calcium nutriture is underscored by the observation that when Greenspan et al. ⁷⁹ investigated the relative efficacy of HRT (conjugated estrogen with or without medroxyprogesterone) plus alendronate, HRT alone, alendronate alone, or placebo on spine and hip BMD in 373 osteopenic elderly women, all subjects received calcium and vitamin D supplements. After 3 years, DXA scans showed that participants taking combination therapy had greater improvement in BMD at the hip and spine than those taking HRT or alendronate alone or taking placebo, all with calcium and vitamin D.

In an uncontrolled clinical trial involving osteoporosis patients with a poor response to bisphosphonate therapy, Heckman et al. ⁸⁰ found that the addition of 25 µg (1000 IU) per day of vitamin D to the bisphosphonate regimen resulted in significantly increased BMD of the lumbar spine after 1 year. In a randomized, double-blind trial involving 48 osteopenic and osteoporotic women, Brazier et al. ⁸¹ compared one group who received 10 mg alendronate once daily along with 500 mg elemental calcium daily and 10 µg (400 IU) cholecalciferol (vitamin D ³ ) twice daily for 3 months and a second group who received the same dosage of alendronate and calcium but placebo instead of the vitamin D. All subjects had low BMD, serum 25-hydroxyvitamin D ³ (25-OHD, calcifediol) less than 12 µg/L, and dietary calcium intake less than 1 g/day. Although markers of bone remodeling, such as serum and urinary CTX and urinary NTX (C- and N-terminal telopeptides of type I collagen), were dramatically and significantly decreased after as little as 15 days of treatment and remained decreased throughout the course of treatment in both groups, the group also receiving the vitamin D demonstrated a more pronounced effect, particularly after 1 month, for the bone resorption markers serum CTX and urinary NTX. These researchers concluded that coadministration of calcium and vitamin D is appropriate in elderly women with calcium and vitamin D insufficiencies receiving alendronate, to achieve rapid reduction of bone loss. ⁸¹

In a randomized trial involving 154 patients with Crohn's disease, Siffledeen et al. ⁸² investigated the efficacy of etidronate plus calcium and vitamin D for treatment of low BMD. The subjects, most of whom had T scores in the osteopenic range (−1.5 to −2.5), were administered etidronate (400 mg orally) or placebo for 14 days, and then both groups were given daily calcium (500 mg) and vitamin D (400 IU) for 76 days, in a treatment cycle repeated every 3 months for 2 years. After 24 months, BMD at the lumbar spine, ultradistal radius, and trochanter sites, but not the total hip, increased steadily, significantly, and similarly in both treatment arms. The findings demonstrate that in patients with low BMD on absorptiometry, treatment with calcium and vitamin D alone will increase BMD by about 4% per year, and that adding etidronate to the treatment program does not appear to enhance the effects of calcium and vitamin D. ⁸² In an accompanying editorial on the preeminence of calcium and vitamin D in limiting fracture risk in Crohn's disease, Bernstein ⁸³ commented that this study provides reassurance that bisphosphonates are “rarely needed in IBD [inflammatory bowel disease] patients, most of whom have T scores greater than −2.5, and many of whom are using corticosteroids to some extent.”

Some patients with prostate carcinoma and a diffuse metastatic invasion of the skeleton exhibit indirect biochemical and histological indications of osteomalacia. Bisphosphonates are known to cause symptomatic hypocalcemia in prostate cancer patients with diffuse skeletal metastases. Bisphosphonate administration can aggravate osteomalacia and give the appearance of symptomatic hypocalcemia because of the transient, striking prevalence of osteoblastic activity over bone resorption by osteoclasts, which are inhibited by bisphosphonate drugs. Calcium supplementation is often considered as contraindicated in individuals with prostate cancer. However, concomitant use of calcium with bisphosphonates has been proposed as a means of inhibiting the osteoclastic activation that often precedes the abnormal osteoblastic bone formation within metastases.

In regard to men with nonmetastatic prostate cancer, findings from a small, randomized, double-blind, controlled trial conducted by Nelson et al. ⁸⁴ showed that treatment with alendronate, 70 mg weekly, plus daily calcium and vitamin D, reversed bone loss in 56 men receiving antiandrogen therapy. In contrast, the 56 subjects taking placebo, calcium, and vitamin D lost bone density during the same period. Notably, among these 112 men, with an average age of 71, only 9% had normal bone mass, whereas 52% had low bone mass and 39% developed osteoporosis after an average 2 years of ADT.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Calcium and vitamin D are essential for maintaining bone mass and density and imperative to the success of drug therapies for inducing bone augmentation. ⁷⁷ Deficiencies of both nutrients are common in the patient populations at highest risk for osteoporosis. The importance of exercise and sound nutrition (including adequate protein, calcium, and phosphorus intake) as foundational cannot be overemphasized and is supported by growing evidence. Calcium has a clearly demonstrated effect of enhancing estrogen's effects on bone metabolism. Further, most research indicates that consistent exposure to sunlight (excluding winter in northern latitudes) provides a safe and effective, as well as otherwise beneficial, method of elevating vitamin D levels. Doses of 1500 mg calcium and 800 IU vitamin D daily provide prudent nutritional support for osteoporosis prevention and treatment, or more exactly, 30 to 40 mmol calcium with sufficient intake vitamin D daily to maintain serum 25(OH)D levels above 80 nmol/L (∼30 µg/L). ⁷⁸

Thus, a synergistic combination of oral calcium and vitamin D, within the context of an active lifestyle, constitutes the core proactive intervention within integrative therapeutics for all individuals at high risk for osteoporosis, or a foundational treatment for diagnosed bone loss. Notably, low serum vitamin D levels have been associated with the incidence of falls in older women, ⁸⁵ and vitamin D has been found to be helpful in reducing the incidence of falls, a major factor in fracture risk, by improving muscle strength, walking distance, and functional ability. ⁸⁶ Also, hormone supplementation or replacement regimens (conventional HRT, bio-identical estrogens/progesterone, herbal hormone precursors/modulators) should be considered if indicated in women.

In addition to these primary and secondary therapies, a bisphosphonate can provide a potent intervention in reversing bone loss and supporting healthy bone mass. Whereas oral calcium preparations need to be taken at least 2 hours before or after the bisphosphonate to avoid pharmacokinetic interference, such timing of oral vitamin D intake is unnecessary because no evidence has indicated potential pharmacological interference with bisphosphonates or other components of the treatment. It is generally recommended that alendronate or etidronate be taken with a full glass (6-8 ounces) of plain water on an empty stomach, avoiding the recumbent position for at least 30 minutes to prevent the potential for severe esophageal irritation associated with incomplete transfer of the tablet to the stomach.

Alfacalcidol, calcitriol, dihydrotachysterol. See also later discussion for therapeutics involving vitamin D analogs and other agents.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Probability: 1. Certain
Evidence Base:

Cholestyramine, Colestipol, and Related Bile Acid Sequestrants

Effect and Mechanism of Action

The simultaneous use of supplemental vitamin D and vitamin D analogs, such as calcitriol, inherently produces an additive effect. The potential for vitamin D toxicity is particularly increased because calcitriol [1,25(OH) ² D ³ ] and its drug formulations bypass physiological feedback mechanisms and control systems that normally limit its production in the kidneys. The clinical significance and severity of the interaction primarily depend on the respective dosages involved and duration of intake, although individual variability based on VDR genotype, diet, and other factors may modify the intensity and character of the response.

Research

Research into coordinated administration of supplemental vitamin D and vitamin D analogs represents a viable approach to integrative therapeutics that has yet to be conducted in a systemic manner.

The use of calcitriol and other vitamin D analogs in combination with other pharmaceutical agents represents an emerging area of therapeutic synergy. Even though these agents are drugs and not nutrients per se, their action is derived from their relationship to vitamin D, and their therapeutic application is discussed briefly later.

Reports

Reports of vitamin D toxicity resulting from simultaneous intake of vitamin D and pharmaceutical analogs are lacking.

Clinical Implications and Adaptations

Coadministration of vitamin D and analogs such as calcitriol may be appropriate in some circumstances, as in renal disease, but only under close medical supervision. Unintentional concomitant use of vitamin D and its pharmacological analogs should be avoided through direct inquiry by health care providers of patients initiating therapy and routine implementation of a thorough inventory of vitamin and other supplement intake.

Evidence: Cholestyramine (Locholest, Prevalite, Questran), colestipol (Colestid). Extrapolated, based on similar properties: Colesevelam (WelChol).

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Probability: 4. Plausible
Evidence Base:

Effect and Mechanism of Action

Absorption of dietary sources of vitamin D requires bile. Bile acid sequestrants, such as cholestyramine and colestipol, decrease lipid digestion and absorption. In the process, they also reduce absorption of the fat-soluble vitamins, such as vitamin D, and other nutrients. ^87-89

Research

Tonstad et al. ⁹⁰ conducted a study of 37 boys and 29 girls age 10 to 16 years with familial hypercholesterolemia, first in an 8-week, double-blind, placebo-controlled protocol, then in open treatment for 44 to 52 weeks. After 1 year of colestipol, those who took 80% or more of the prescribed dose had a greater decrease in serum 25-OHD levels than those who took less than 80%. They also found that levels of serum folate, vitamin E, and carotenoids were reduced in the colestipol group. ⁹⁰

In a rodent model, Watkins et al. ⁹¹ found that cholestyramine may deplete calcium (and zinc), an effect that could adversely impact the function of vitamin D, especially in regard to bone health.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Fat-soluble vitamins, and vitamin D nutriture in particular, can play a valuable role in the prevention and treatment of many conditions involving the cardiovascular system and lipid metabolism (including atherosclerosis, heart disease, obesity, hypertension, and diabetes), such that interference with its absorption could be counterproductive in relation to the broad therapeutic strategy and clinical outcomes. Modest supplementation with vitamin D (10-20 µg or 400-800 IU daily) may be advisable for many individuals, particularly those at high risk for deficiency sequelae, but consistent exposure to sunlight (without sunscreen) may be sufficient to maintain healthy vitamin D levels and can be combined with the exercise usually critical to those prescribed bile acid sequestrants. Exposure to sunlight in the winter months of higher latitudes, however, is likely to be insufficient to maintain adequate vitamin D levels, making dietary use of supplements or a rich natural source of vitamin D (e.g., cod liver oil) necessary, separated from the bile acid sequestrant by at least 2 hours.

Cimetidine

Cimetidine (Tagamet)

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Probability: 4. Plausible
Evidence Base:

Corticosteroids, Oral, Including Prednisone

Effect and Mechanism of Action

Cimetidine inhibits vitamin D hydroxylase (a hepatic mixed-function oxidase) and may reduce hepatic activation of vitamin D through hydroxylation. ⁹²

Research

In limited animal and human research, cimetidine has been found to decrease the synthesis of vitamin D and adversely affect serum levels of 25-OHD.

In a small, uncontrolled trial, Odes et al. ⁹³ treated nine adult subjects with 400 mg cimetidine orally twice daily during a period from winter to summer, as the daily duration of sunlight was increasing. They measured serum levels of 25-OHD, 24,25(OH) ² D, and 1,25(OH) ² D before treatment, after 4 weeks of treatment, and 1 month after cessation of treatment. The normal seasonal increase in the level of 25-OHD was not observed during treatment. However, 25-OHD did rise significantly after the cimetidine was withdrawn. These researchers concluded that their findings “suggest that short-term treatment with cimetidine could potentially perturb vitamin D metabolism in man.”

Further clinical trials would be necessary confirm these preliminary findings and to determine whether other H ² receptor antagonists might similarly affect vitamin D metabolism in humans.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Laboratory tests can determine blood levels of 25-hydroxycholecalciferol, the form of vitamin D after it has been hydroxylated in the liver. Low levels require prescription of an activated form of vitamin D (e.g., calcitriol) because activation of a regular vitamin D supplement (or even cholecalciferol derived from sunlight exposure) would be vulnerable to blockage by the cimetidine. In this case it would be prudent to monitor the serum level of 1,25-dihydroxyvitamin D to be certain that replacement is adequate but not excessive.

Betamethasone (Celestone), cortisone (Cortone), dexamethasone (Decadron), fludrocortisone (Florinef), hydrocortisone (Cortef), methylprednisolone (Medrol) prednisolone (Delta-Cortef, Orapred, Pediapred, Prelone), prednisone (Deltasone, Liquid Pred, Meticorten, Orasone), triamcinolone (Aristocort). Similar properties but evidence indicating no or reduced interaction effects: Inhaled or topical corticosteroids.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Probability: 2. Probable, 3. Possible
Evidence Base:

Hormone Replacement Therapy (HRT): Estrogen-Containing and Synthetic Estrogen and Progesterone Analog Medications

Effect and Mechanism of Action

Oral corticosteroids are associated with osteoporosis. The mechanism is multifactorial, including reduced calcium absorption, decreased vitamin D availability, lowered serum 25-hydroxycalciferol levels, and interference with vitamin D activation and metabolism, all increasing risk of bone loss. ^94-99 Corticosteroids also contribute to osteoporosis through increased renal calcium excretion and decreased bone formation by osteoblasts and serum levels of sex hormones. Administration of cortisone impairs net calcium absorption through two mechanisms: depressed vitamin D–dependent calcium absorption and increased vitamin D–independent calcium backflux. ¹⁰⁰

Research

It is generally recognized that long-term use of corticosteroids can lead to loss of bone mineral density (BMD) and higher risk for fractures. Of patients using corticosteroids for long periods, 25% develop at least one fracture. Although the usefulness of calcium and vitamin D supplements in the treatment and the prevention of steroid-induced osteoporosis may seem self-evident, research into the effectiveness of such nutritional therapies has been slow to evolve. Nevertheless, it now appears that the adverse effects of glucoactive corticosteroids on intestinal calcium transport and bone turnover can usually be counteracted by the combined administration of supplemental doses of calcium and physiological doses of 25-OHD ³ .

In 1977, Hahn et al. ¹⁰¹ observed no significant serum 25-OHD concentrations in 21 adults receiving chronic, moderate-dose corticosteroid therapy and who demonstrated radiological osteopenia (vs. controls). However, in 1978, Chesney et al. ⁹⁸ found a reduction of serum 1,25(OH) ² D in children receiving long-term glucocorticoid treatment for various glomerular diseases (vs. children with chronic glomerulonephritis but not treated with glucocorticoids). They further observed that this reduction in serum 1,25(OH) ² D ³ concentration correlated with the dose of steroid administered as well as with the severity of reduction in forearm bone mineral content.

By administering 20 mg/day of prednisone to 12 normal adults for 14 days, Hahn et al. ⁹⁴ confirmed that glucocorticoids suppress intestinal calcium absorption (by 31%), but not by decreasing circulating concentrations of biologically active vitamin D metabolites, since mean serum concentrations of 25-OHD and 24,25(OH) ² D did not change significantly from initial values; serum 1,25(OH) ² D concentration was even slightly increased.

In a 2-year, randomized, double-blind, placebo-controlled trial, Buckley et al. ¹⁰² administered 500 IU of vitamin D ³ and 1000 mg of calcium carbonate daily to 65 rheumatoid arthritis patients being treated with low amounts of prednisone (mean dosage, 5.6 mg daily). They found that those who received the nutrients maintained or gained BMD in the lumbar spine and trochanter, whereas those receiving prednisone therapy but were given placebo (i.e., no supplements) lost BMD in the same areas during the course of the study. In a subsequent study (1998), Lems et al. ¹⁰³ reported that low-dose (10 mg/day) prednisone (LDP) treatment led to a decrease in osteocalcin, P1CP, and alkaline phosphatase and an increase in urinary excretion of calcium. They concluded that LDP has a negative effect on bone metabolism because bone formation decreased while bone resorption remained unchanged or decreased slightly. They also found parathyroid hormone (PTH) increased (insignificantly) during LDP (+19%) and LDP plus calcium (+14%), but decreased during coadministration of with calcitriol (−16%) and calcium/calcitriol (−44%). The increase in PTH during LDP could be prevented by calcitriol combined with calcium supplementation.

Wissing et al. ¹⁰⁴ conducted a 1-year controlled trial investigating the effect of low-dose corticosteroids on post–renal transplant bone loss and the ability of cholecalciferol to further decrease bone loss. They administered either 400 mg oral calcium or 400 mg oral calcium daily in association with a monthly dose of 25,000 IU vitamin D ³ to 90 patients admitted for renal transplantation and scheduled to be treated with low doses of prednisolone. All subjects experienced a “moderate but significant” loss of lumbar spine BMD, but no bone loss at the femoral neck and shaft during the first posttransplant year. Subjects in the calcium/D ³ group had significantly higher 25-OHD but not 1,25(OH) ² D levels and exhibited slightly higher bone loss, but the difference did not reach statistical significance. The researchers also reported “a highly significant negative correlation between 25(OH) vitamin D and intact parathyroid hormone (iPTH) serum levels.” They concluded that “cholecalciferol supplementation did not prevent posttransplant bone loss but contributed to the normalization of iPTH levels after renal transplantation.” ¹⁰⁴ Notably, the dose administered, 25,000 IU of D ³ once a month, is less than the 1000 IU per day recommended by experts as the minimum for those not exposed to adequate sunlight, and it is not well timed for an agent with a half-life of 2 weeks.

A meta-analysis of well-designed clinical trials by Amin et al. ¹⁰⁵ concluded that supplementation with vitamin D and calcium was more effective than placebo or calcium alone in providing a “moderate” protective effect against corticosteroid-induced osteoporosis, using change in lumbar spine BMD as the primary outcome measure. However, bisphosphonates and fluoride were more effective than vitamin D in some trials.

In contrast, numerous studies and several reviews of inhalant and nasal corticosteroids have consistently concluded that such medications, in and of themselves, do not generally pose a significant risk of inducing bone loss in children or adults. ¹⁰⁶ For example, Elmstahl et al. ¹⁰⁷ reported no difference in BMD in a group of subjects taking inhaled corticosteroids and unexposed control subjects, nor was any dose-response relationship observed between inhalant steroid therapy and BMD. Likewise, Suissa et al. ¹⁰⁸ conducted a case-control study nested within a population-based cohort of all Quebec patients at least 65 years of age who were given respiratory medications and followed for at least 4 years. The rate of fracture for current inhaled corticosteroid use was not increased, and the rate of upper extremity fracture increased by 12% (RR 1.12) with every 1000-µg increase in the daily dose of inhaled corticosteroids. No such increase was observed for hip fracture. Among a subgroup of subjects followed more than 8 years, “only the use of more than 2000 µg of inhaled corticosteroids per day for an average of 6 years was associated with an elevated risk of fracture.” No increase in the rate of fractures was observed at any dose of nasal corticosteroids.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing corticosteroids, possibly for only 1 month but especially for longer periods, are advised to discuss the potential adverse metabolic implications of such medications with patients and compensatory options. In 1998, Lems et al. ¹⁰⁹ noted that “in spite of guidelines according to which patients protractedly using corticosteroids should take sufficient calcium and cholecalciferol, only about one-tenth of them takes any form of medication to prevent osteoporosis.” Most research indicates that calcium intakes from dietary and supplemental sources totaling 1000 to 1500 mg of calcium per day in conjunction with 10 to 20 µg (400-800 IU) of vitamin D are required to prevent adverse effects, although much higher doses may be necessary in the context of a preexisting 25OHD deficiency. ⁴⁰ Monitoring serum levels of both 25-OHD and 1,25(OH) ² D (activated form of vitamin D) is appropriate, and supplementation (or possibly a prescription of calcitriol) is often necessary if a deficiency is indicated. If 25-OHD levels are low (<50 nmol/L), correction with up to 7000 IU vitamin D ³ per day, or 50,000 IU vitamin D ² per week, for 1 to 2 months will correct the 1,25(OH) ² D level in patients with normal renal function. Often the 1,25(OH) ² D (dihydroxycholecalciferol) level is maintained, even in the face of a 25-OHD deficiency, due to increased secretion of PTH, which speeds up renal conversion of 25-OHD to the active form. Thus, measuring intact PTH, as well as both forms of vitamin D, provides the most complete picture of vitamin D status. ⁴⁰ It is also prudent to monitor for hypercalciuria and hypercalcemia when supplementing with both calcium and vitamin D, although the occurrence of hypercalcemia is rare.

Physicians prescribing steroids for longer than 2 weeks should encourage all patients to modify their lifestyles, including smoking cessation and limitation of alcohol consumption. The importance of mild to moderate weight-bearing exercise cannot be overemphasized; 30 minutes to 1 hour every day, particularly with sunlight exposure, should be strongly encouraged, if feasible. However, individuals with known or potential bone loss should be advised to develop an exercise program under the supervision of a physician or other health care professional familiar with the increased risks of fracture associated with long-term use of steroids.

Some physicians may consider it necessary and appropriate to prescribe calcitriol in individual cases. Concomitant use of bisphosphonates and estrogen/progesterone support may also be appropriate for some individuals using oral steroids longer than 3 months, especially if low BMD is evident or likely.

Evidence: HRT, estrogens: Chlorotrianisene (Tace); conjugated equine estrogens (Premarin); conjugated synthetic estrogens (Cenestin); dienestrol (Ortho Dienestrol); esterified estrogens (Estratab, Menest, Neo-Estrone); estradiol, topical/transdermal/ring (Alora Transdermal, Climara Transdermal, Estrace, Estradot, Estring FemPatch, Vivelle-Dot, Vivelle Transdermal); eestradiol cypionate (Dep-Gynogen, Depo-Estradiol, Depogen, Dura-Estrin, Estra-D, Estro-Cyp, Estroject-LA, Estronol-LA); estradiol hemihydrate (Estreva, Vagifem); estradiol valerate (Delestrogen, Estra-L 40, Gynogen L.A. 20, Progynova, Valergen 20); estrone (Aquest, Estragyn 5, Estro-A, Estrone ‘5’, Kestrone-5); estropipate (Ogen, Ortho-Est); ethinyl estradiol (Estinyl, Gynodiol, Lynoral). HRT, estrogen/progestin combinations:Conjugated equine estrogens and medroxyprogesterone (Premelle cycle 5, Prempro); conjugated equine estrogens and norgestrel (Prempak-C); estradiol and dydrogesterone (Femoston); estradiol and norethindrone, patch (CombiPatch); estradiol and norethindrone/norethisterone, oral (Activella, Climagest, Climesse, FemHRT, Trisequens); estradiol valerate and cyproterone acetate (Climens); estradiol valerate and norgestrel (Progyluton); estradiol and norgestimate (Ortho-Prefest). Related but evidence lacking for extrapolation: HRT, estrogen/testosterone combinations: Esterified estrogens and methyltestosterone (Estratest, Estratest HS). HRT, progestins:Dydrogesterone (Duphaston), intrauterine L-norgestrel system (Mirena), medroxyprogesterone acetate (Provera), norethisterone (norethindrone; Micronor). HRT, progesterone:Micronized progesterone (Prometrium, Utrogestan). Medroxyprogesterone:Conjugated equine estrogens and medroxyprogesterone (Premelle cycle 5, Prempro); medroxyprogesterone, oral (Cycrin, Provera); medroxyprogesterone, injection (depot medroxyprogesterone acetate, DMPA; Depo-Provera, Depo-subQ Provera 104); progestin and estrogen injectable: estradiol cypionate and medroxyprogesterone acetate (Cyclofem, Lunelle).

	Beneficial or Supportive Interaction, with Professional Management
	Minimal to Mild Adverse Interaction—Vigilance Necessary

Probability: 3. Possible or 2. Probable
Evidence Base:

Effect and Mechanism of Action

The combination of vitamin D and estrogen replacement therapy (ERT, in the context of calcium supplementation) increases bone mass more than ERT alone, especially in osteoporotic women. The ability of exogenous female hormones, particularly forms of estrogen, to effectively inhibit osteoclastic activity and bone resorption, maintain healthy bone mineralization, and support bone mass is inherently dependent on the presence of vitamin D and other nutrients (e.g., protein, calcium, phosphorus). ^76,77 Calcium, the principal element in bone, can be absorbed in the brush border of the intestinal mucosa only when vitamin D is present. Estrogen appears to have a beneficial effect on vitamin D (and calcium) metabolism, although progestins may diminish that benefit. Estrogen also inhibits osteoclastic action, which would represent an additive interaction with vitamin D.

Research

The negative calcium balance usually associated with aging is accentuated in osteoporotic women who have decreased calcium absorption and decreased serum levels of 1,25(OH) ² D. In a controlled trial involving 17 women with surgically induced menopause, Lobo et al. ¹¹⁰ (1985) observed that serum levels of 1,25(OH) ² D increased and urinary calcium loss decreased after 2 months of conjugated estrogens (0.625 mg daily). ¹¹⁰ Subsequently, several studies have investigated various aspects of the question of whether such elevated vitamin D levels might correspond with increased bone strength and reduced risk of fractures and how this effect might vary given initial BMD status, for different individuals, under different HRT regimens, or with different forms of calcium.

Several studies have examined the role of HRT in improving vitamin D activity and calcium balance in women with postmenopausal osteoporosis. In an early study of postmenopausal women by Bikle et al., ¹¹¹ treatment with 17β-estradiol alone increased serum 1,25(OH) ² D, but the addition of medroxyprogesterone, a progestin, lowered vitamin D levels such that total and free 1,25(OH) ² D returned toward baseline and thus appeared to antagonize part of the beneficial effects on calcium homeostasis attributable to estrogen. In the first prospective trial confirming the beneficial effect of HRT on prevention of peripheral fractures in nonosteoporotic postmenopausal women and subsequent controlled studies, Komulainen et al. ^112-114 determined that supplementation with 300 IU/day of vitamin D ³ (cholecalciferol) does not prevent bone loss in healthy, nonosteoporotic, early-postmenopausal women, nor does such low-dose vitamin D ³ provide significant benefit beyond that attributable solely to combined estradiol and progestin. However, in a 4-year, prospective, partly randomized study of 60 osteoporotic women, Tuppurainen et al. ¹¹⁵ found that vitamin D ³ (cholecalciferol, 300 IU/day, no intake during June–August) together with a combination of 2 mg estradiol valerate and 1 mg of a progestin (cyproterone acetate) daily resulted in greater improvement in BMD compared with estradiol/progestin alone (as well as with baseline or placebo). The osteoporotic women in both HRT groups demonstrated a significant increase in lumbar BMD, but there were no statistically significant differences in either lumbar or femoral BMD changes between these two HRT groups. Furthermore, the combination of HRT and vitamin D ³ was associated with a greater increase in femoral neck BMD than with HRT alone.

In a randomized, double-blind, placebo-controlled trial involving 128 healthy Caucasian women over age 65 with low spinal BMD, Recker et al. ¹¹⁶ compared parameters of BMD and bone loss under continuous low-dose HRT (conjugated equine estrogen, 0.3 mg/day, and medroxyprogesterone, 2.5 mg/day) in conjunction with calcium and vitamin D supplementation versus placebo. Subjects in both groups were administered sufficient calcium supplementation to bring all calcium intakes above 1000 mg/day and oral 25-OHD sufficient to maintain serum 25-OHD levels of at least 75 nmol/L. Through the course of 3.5 years of observation, significant increases were seen in spinal BMD as well as in total-body and forearm bone density, particularly among patients with greater than 90% adherence to therapy. Meanwhile, breast tenderness, spotting, pelvic discomfort, mood changes, and other symptoms typically associated with HRT were mild and short-lived under this relatively low-dose regimen. These authors concluded that “continuous low-dose HRT with conjugated equine estrogen and oral medroxyprogesterone combined with adequate calcium and vitamin D provides a bone-sparing effect that is similar or superior to that provided by other, higher-dose HRT regimens in elderly women” and is well tolerated by most patients. ¹¹⁶

In a 6-month, placebo-controlled clinical trail involving 21 postmenopausal women with osteoporosis, Gallagher et al. ¹¹⁷ observed that conjugated equine estrogen increased both calcium absorption and serum vitamin D levels [1,25(OH) ² D]. Subsequently, these researchers investigated the roles of estrogen deficiency and declining calcium absorption from reduced activated vitamin D (calcitriol) levels or intestinal resistance to calcitriol as central factors in age-related bone loss. In a randomized, double-blind, placebo-controlled trial involving 485 elderly women (66-77 years old) with normal BMD for their age, Gallagher et al. ¹¹⁸ compared the effects of ERT (0.625 mg conjugated estrogens daily for women without a uterus) and HRT (ERT plus 2.5 mg medroxyprogesterone acetate daily for those women with a uterus) with or without calcitriol (1,25-OHD) versus placebo. Hormone therapy alone and in combination with calcitriol were both highly effective in reducing bone resorption and increasing BMD at the hip and other key sites. In particular, calcitriol was effective in increasing BMD in the femoral neck and spine. The combination of ERT/HRT and calcitriol increased BMD in the total hip and trochanter significantly more than did ERT or HRT alone, particularly in women adherent to treatment. Thus, the concomitant use of vitamin D, calcium, and conventional forms of HRT appear generally to raise vitamin D levels but especially to enhance BMD in women who demonstrate osteoporosis, that is, those for whom BMD is most critical. Furthermore, such nutritional support may also allow for reduced HRT dosages and corresponding decrease in risk of attendant adverse effects and sequelae.

The form of calcium used for supplementation presents a potential confounding factor that has not been considered by most researchers but that would be a central concern to most practitioners of nutritional therapeutics. By examining data from a trial involving 25 postmenopausal women, Heller et al. ¹¹⁹ (2002) found that variable results of reported calcium supplementation studies may be caused by the effects of estrogen treatment or vitamin D status on the bioavailability of calcium citrate versus calcium carbonate. Using data derived from a prior trial in 25 postmenopausal women, the authors found that change in area under the curve (ΔAUC) of serum calcium after subtraction of placebo was significantly higher after calcium citrate than after calcium carbonate in non–estrogen-treated patients. Estrogen-treated patients showed no evident difference in the bioavailability of calcium between the two calcium formulations. Bioavailability was also significantly higher with the citrate salt for the subgroups with lower serum 25-OHD and higher serum 1,25(OH) ² D concentrations. Thus, bioavailability of calcium from calcium carbonate was more dependent on estrogen treatment and vitamin D status than that of calcium citrate.

Preliminary research into polymorphisms of the estrogen receptor (ER), vitamin D receptor (VDR), and their interactions may help clarify individual genetic variations in the influence of hormone therapies, exercise, ethnic background, and other factors on bone mineral density (BMD) and peak bone mass. In a population-based, 3-year, longitudinal study of BMD, Willing et al. ¹²⁰ found that two genetic ER polymorphisms were significantly predictive of both lumbar spine and total-body BMD level, but not change in BMD during the study. A genetic VDR variant was not associated with baseline BMD, change in BMD over time, or any of the bone-related serum and body composition measurements in the 372 women in whom it was evaluated. Further, no other polymorphic markers were identified as being significantly associated with BMD measurements. However, these researchers did identify a significant impact on BMD levels associated with an interaction of two ER polymorphisms and two VDR genotypes. Subjects who had the (−/−) PvuII ER and bb VDR genotype combination had a very high average BMD, whereas women with the (−/−) PvuII ER and BB VDR genotype had significantly lower BMD levels. Differences in serum levels of osteocalcin, PTH, 1,25(OH) ² D, or 25(OH) ² D did not explain this contrast. These authors concluded that their findings “suggest that genetic variation at the ER locus, singly and in relation to the vitamin D receptor gene, influences attainment and maintenance of peak bone mass in younger women, which in turn may render some individuals more susceptible to osteoporosis than others.” ¹²⁰

Subsequently, in a study involving 108 postmenopausal Caucasian women, Deng et al. ¹²¹ found that VDR and ER genotypes may have different effects on BMD at different sites and on total-body bone mineral content (tbBMC). They assessed associations of BMD with VDR BsmI genotypes and ER XbaI (ERX) and PvuII (ERP) polymorphisms with spine, femoral neck, and distal radius BMD and with tbBMC. In this sample, researchers did not detect a significant association for ER genotypes with spine and radius BMD, or for VDR genotypes with femoral neck and radius BMD and tbBMC, or find a significant interaction between VDR and ER genotypes. However, they did note significant associations between (1) VDR genotypes and spine BMD variation, (2) both ERX and ERP genotypes and femoral neck BMD variation, and (3) ERX genotypes and tbBMC variation. Based on these observations, these researchers concluded that “if significant factors influencing bone are not appropriately controlled, true significant associations can easily be missed.” ¹²¹ Related research suggests that bone may be more responsive to exercise in some genotypes of VDR than in others, ¹ and that gene-environment interactions such as leisure physical activity and VDR genotype may play a role in maintaining the BMD at the lumbar spine in active postmenopausal women, especiallyolder women. ²

The importance of individual genotypes as important factors in determining changes in bone mass in the elderly, with and without HRT, as well as other factors, such as vitamin D and mineral nutriture and exercise, is becoming increasingly clear and will undoubtedly receive greater consideration in shaping individualized therapeutic strategies to optimize and preserve bone mass.

Myrup et al. ¹²² cautioned against a possible limiting effect of cholecalciferol on the lipid benefits of HRT, along with potential risk of hypercalcemia. In a double-blind, randomized trial involving 74 postmenopausal women, they investigated the effect of cholecalciferol and estrogen-norethindrone treatment for 1 year on total cholesterol level, high-density lipoprotein (HDL) cholesterol level, blood pressure, and body mass index. A similar decrease in serum cholesterol level was demonstrated in subjects receiving estrogen-norethindrone (11%) and those receiving hormones combined with cholecalciferol (13%); this hypocholesterolemic effect was most pronounced in lean women. However, the HDL cholesterol/total cholesterol ratio increased only 25% in women administered both estrogen-norethindrone and cholecalciferol, versus an increase of 45% with estrogen-norethindrone treatment alone. ¹²² Subsequently, in a in a population-based, prospective, 3-year study involving 464 women, Heikkinen et al. ¹²³ arrived at similar conclusions. They found that serum concentrations of HDL cholesterol did not change significantly in the group receiving HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate) alone, but decreased in the groups receiving vitamin D ³ , HRT plus vitamin D ³ , or placebo.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Hormone support, calcium, and vitamin D act in concert to enhance the primary activities of nutrition and exercise in healthy bone metabolism. HRT has been the mainstay of osteoporosis prevention but is limited because of dose-related risks, adverse effects, and patient acceptance. Furthermore, because estrogen alone can be safely used only in women without a uterus, due to an unacceptably high incidence of uterine cancer with unopposed estrogen, all postmenopausal women with an intact uterus receiving hormonal therapy must be treated with some combination of estrogen and progestins or their analogs, even though estrogen's effect on bone appears potentiated by calcium and vitamin D, and progestins may work against it. Calcium and vitamin D are essential for maintaining bone mass and density and imperative to the success of drug therapies for inducing bone augmentation. ⁷⁷ Deficiencies of both nutrients are common in the patient populations at highest risk for osteoporosis. The importance of exercise and sound nutrition (including adequate protein and phosphorus intake) as foundational cannot be overemphasized and is supported by growing evidence. ^2,124,125

Calcium and estrogen have a clearly demonstrated synergistic effect of enhancing each other's effects on bone metabolism. Further, most research indicates that consistent exposure to sunlight provides a safe and effective, as well as otherwise beneficial, method of elevating vitamin D levels. Nevertheless, prudent nutritional support for osteoporosis prevention and treatment can be provided through diet or supplementation including 1500 mg/day of calcium and 800 IU (20 µg) vitamin D, or more exactly, sufficient intake vitamin D per day to maintain serum 25(OH)D levels above 80 nmol/L. ⁷⁸

Thus, a synergistic combination of oral calcium and vitamin D, within the context of an active lifestyle, constitutes the core proactive intervention within integrative therapeutics for all individuals at high risk for osteoporosis, or a base treatment for diagnosed bone loss. Additionally, hormone supplementation or replacement regimens (conventional HRT, bio-identical estrogens/progesterone, isoflavones, herbal hormone precursors/modulators) may produce the same effects, but conclusive evidence is lacking. Further research through well-designed clinical trials is warranted.

Although exogenous hormone therapy (and possibly understudied/untested “natural” alternatives) appears to enhance vitamin D metabolism, the importance of consuming adequate levels of vitamin D through diet and supplements cannot be overstated while taking hormones. As indicated by some of the research reviewed, total cholesterol, low-density lipoprotein (LDL) cholesterol, and HDL cholesterol ratios deserve monitoring in the event that vitamin D supplementation might exert a dyslipidemic effect. Again, exercise might be indicated as playing a fundamental role in the comprehensive therapeutic approach. Notably, low serum vitamin D levels have been associated with the incidence of falls in older women, ⁸⁵ and vitamin D has been found to be helpful in reducing the incidence of falls, a major factor in fracture risk, by improving muscle strength, walking distance, and functional ability. ⁸⁶ Overall, further research is needed to determine the character and full implications of the interaction(s) between supplemental vitamin D and exogenous hormone therapy and their relationship to the many factors influencing bone health and the risks of osteoporosis and fractures.

Heparin, Unfractionated

Heparin, unfractionated (Calciparine, Hepalean, Heparin Leo, Minihep Calcium, Minihep, Monoparin Calcium, Monoparin, Multiparin, Pump-Hep, Unihep, Uniparin Calcium, Uniparin Forte).

	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Probability: 2. Probable
Evidence Base:

Isoniazid and Related Antitubercular Agents

Effect and Mechanism of Action

Over time, heparin causes bone loss, especially in the spine, hips, pelvis, and legs. This effect is more pronounced with standard (unfractionated) heparin (UFH) than with low-molecular-weight heparin (LMWH). At least one mechanism of the negative effect of UFH on bone is nonspecific binding of the longer polysaccharide chains to bone, with inhibition of osteoblastic function. Heparin may also inhibit formation of 1,25-dihydroxyvitamin D by the kidneys. ¹²⁶

Research

Majerus et al. ¹²⁷ reported that use of heparin, at high doses, for several months causes osteoporosis. Likewise, both Wise and Hall ¹²⁸ and later Haram et al. ¹²⁹ found that women who received heparin therapy during pregnancy experienced decreased bone density (i.e., osteopenia). On the other hand, in one study, nine women on heparin treatment received 6.46 g daily of a special calcium preparation, ossein-hydroxyapatite compound (OHC) for 6 months and were compared to 11 women not receiving the bone-protective treatment. In the OHC group, good compliance was observed, with no side effects and reduced back pain. Those taking the calcium preparation did not demonstrate the expected decrease in bone mass, and bone mass decreased significantly in the controls. ¹³⁰

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although the adverse effects of heparin on vitamin D and bone metabolism are well documented, research confirming the benefits of supplementing vitamin D and calcium in individuals on heparin therapy for any extended period is limited. However, in the meantime, such nutritional support would most likely be beneficial and is not contraindicated. Physicians prescribing UFH may find it prudent to coadminister with calcium and vitamin D supplementation. With chronic use, the vitamin D metabolite that should be measured to determine vitamin D status is 25(OH)D (25-hydroxyvitamin D), which is the major circulating form of vitamin D, circulating at 1000 times the concentration of 1,25(OH) ² D (1,25-dihydroxyvitamin D) and having a half-life of 2 weeks; after D ³ repletion has been initiated, monitoring l,25(OH) ² D may be adequate. In some cases, if low, calcitriol may be necessary and appropriate to restore normal activated vitamin D levels; calcitriol is usually required (or appropriate) only in those patients unable to convert 25(OH)D to calcitriol. With long-term heparin therapy, assessment and monitoring of BMD may also be indicated.

Isoniazid (isonicotinic acid hydrazide, INH; Laniazid, Nydrazid); combination drugs: isoniazid and rifampicin (Rifamate, Rimactane); isoniazid, pyrazinamide, and rifampicin (Rifater). Extrapolated, based on similar properties: Cycloserine (Seromycin), ethambutol (Myambutol), ethionamide (2-ethylthioisonicotinamide; Ethide, Ethiocid, Ethomid, Etomide, Mycotuf, Myobid, Trecator SC), pyrazinamide (PZA; Tebrazid). See also Rifampin.

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Probability: 2. Probable
Evidence Base:

Effect and Mechanism of Action

Research indicates that antituberculous drugs, including isoniazid (INH), induce vitamin D deficiency. Vitamin D levels have been found to be lowered in children with tuberculosis (TB), both in untreated children and in those taking isoniazid. Observed declines in activated vitamin D (1α,25-dihydroxyvitamin D) can produce relative hypocalcemia and induce elevation in PTH levels. Isoniazid can inhibit hepatic mixed-function oxidase activity, as evidenced by a reduction in antipyrine and cortisol oxidation, as well as hepatic 25-hydroxylase and renal 1α-hydroxylase; thereby causing such a reduction in the corresponding vitamin D metabolites. ^131,132

Research

Brodie et al. ¹³¹ investigated the effect of isoniazid on vitamin D metabolism, serum calcium and phosphate levels, and hepatic monooxygenase activity by administering isoniazid, 300 mg daily, to eight healthy subjects for 14 days. They observed several responses, including a 47% drop in the concentration of 1α,25(OH) ² D (the most active metabolite of vitamin D) after a single dose of isoniazid, with lowered levels continuing throughout the study; declines in levels of 25OHD (the major circulating form of the vitamin) in all subjects and to below normal range in six; and a 36% elevation in PTH levels in response to the relative hypocalcemia produced. In a study involving 46 children with asymptomatic TB, Toppet et al. ¹³³ found that children administered isoniazid for 3 months demonstrated a decrease in blood levels of 1,25(OH) ² D. Isoniazid appears to interfere similarly with the activity of many other nutrients, including magnesium.

Specific evidence is lacking to determine if isoniazid or related agents actually cause symptoms of vitamin D deficiency and calcium depletion, especially with long-term therapy. Clinical trials are warranted to investigate the clinical significance of any depletion pattern and efficacy of prophylactic intervention. Such research is particularly important in children undergoing long-term therapy, in whom potential adverse effects may significantly impair the calcium economy during this critical life stage, when maximum bone density is being attained and will be relied on for life.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing isoniazid or related antitubercular therapy, especially for longer than 1 month, are advised to recommend coadministration of vitamin D and calcium, preferably as part of a multivitamin and mineral formulation (at least 50 mg vitamin B ⁶ daily is indicated with INH as well); this prudent measure is unlikely to interfere with the efficacy of the medication(s). Vitamin D supplementation may be of great value in addition to antituberculous drugs in the treatment of tuberculous children, and its use is highly recommended. ¹³⁴ Exposure to sunlight is the simplest and most natural way to provide activated vitamin D; sunshine and mountain air were characteristic of the great TB sanitoriums in the pre–anti-TB drug era. However, when vitamin D is to be supplemented orally, the typical dosage would be in the range of 5 to 10 µg (200-400 IU) per day, depending on size and body weight. Concurrent calcium supplementation in the range of 100 to 250 mg three times daily would be appropriate, but research is lacking to confirm specific effective dosage levels.

Granulomatous lesions, such as those present in extensive TB infection, often contain active 1-hydroxylase enzymes that activate 25-OH-cholecalciferol and are independent of the feedback mechanisms that regulate the renal 1-hydroxylase enzymes. Regular monitoring of serum calcium would reveal early vitamin D toxicity in this setting. Research findings emphasize the need for regular monitoring of 25(OH)D and bone status in this population, even if no sign of rickets is observed in these patients.

Ketoconazole

Ketoconazole (Nizoral).

Bimodal or Variable Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Effect and Mechanism of Action

Ketoconazole blocks adrenal steroidogenesis by inhibiting P450 enzymes involved in steroid hormone synthesis. In so doing, however, ketoconazole also inhibits 1α-hydroxylase and 24-hydroxylase, the P450 enzymes that metabolize vitamin D; inhibits renal 1,25(OH) ² D synthesis; and reduces serum levels of calcitriol. ^135,136

This activity enables ketoconazole to serve as a second-line ADT in the treatment of prostate cancer. The ability of vitamin D to inhibit growth of prostate cancer cells depends on levels of the active metabolite, 1,25(OH) ² D (calcitriol). Because 24-hydroxylase converts calcitriol to less active products, its inhibition by ketoconazole maintains the magnitude and duration of response to calcitriol. ¹³⁷

Research

Adams et al. ¹³⁸ reported that ketoconazole decreases the serum 1,25(OH) ² D and calcium concentration in sarcoidosis-associated hypercalcemia. In several studies, Glass et al. ^139-141 found that ketoconazole reduced previously elevated serum 1,25(OH) ² D and total serum calcium in hypercalcemic patients, particularly those with sarcoidosis. In a study of 19 patients with well-characterized absorptive hypercalciuria, Breslau et al. ¹⁴² found they could separate subjects into those who responded to ketoconazole and those who were nonresponders. Responders demonstrated reduced serum 1,25(OH) ² D, decreased intestinal calcium absorption, and decreased 24-hour urinary calcium excretion.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing ketoconazole for extended periods, including use in conjunction with calcitriol for the treatment of prostate cancer, are advised to closely supervise and regularly monitor for drug-induced vitamin D deficiency. Given the nature of ketoconazole's action, simple oral vitamin D supplementation may not provide adequate protection, and calcitriol might need to be prescribed to avoid adverse effects of vitamin D deficiency. Monitoring is essential because the half-life of administered calcitriol tends to be prolonged in presence of ketoconazole.

Neomycin

Neomycin (Mycifradin, Myciguent, Neo-Fradin, NeoTab, Nivemycin); combination drugs: Adcortyl with Graneodin, Betnovate-N, Dermovate-NN, Gregoderm, Synalar N, Tri-Adcortyl, Trimovate.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Probability: 2. Probable
Evidence Base:

Effect and Mechanism of Action

It is widely accepted that extended use of neomycin can significantly decrease absorption or increase elimination of vitamin D as well as many other nutrients, including beta-carotene, folic acid, vitamin A, vitamin B ¹² , vitamin K, calcium, iron, magnesium, potassium, and sodium. ⁸⁹

Research

No specific evidence is cited because the literature treats this interaction as axiomatic.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing extended courses of neomycin are advised to coadminister a multivitamin and mineral supplement as a prudent measure to avoid potential drug-induced deficiencies. Separation of oral intake by at least 2 hours will reduce the risk of intrerference with absorption of either preparation.

Orlistat

Orlistat (alli, Xenical).

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Probability: 2. Probable
Evidence Base:

Effect and Mechanism of Action

Orlistat is a gastrointestinal lipase inhibitor that binds dietary fat and prevents its absorption. Such activity can interfere with the absorption of vitamin D and other fat-soluble nutrients and potentially induce deficiency patterns.

Research

In a 52-week, double-blind, randomized, parallel-group, placebo-controlled multicenter study, preceded by a 4-week, single-blind, placebo run-in period, James et al. ¹⁴³ observed that vitamin D (and beta-carotene) concentrations decreased in patients treated with 120 mg orlistat three times daily, compared with those receiving placebo (even though fat-soluble vitamin levels remained within the normal range in the treatment group). Van Gaal et al. ¹⁴⁴ conducted a 6-month, multicenter, randomized, double-blind, parallel-group clinical trial involving 676 obese men and women. Most subjects demonstrated reduced blood levels of vitamins D and A, but these remained within the clinical reference ranges, and only few individuals developed nutrient deficiency patterns that required supplementation. However, in a clinical trial involving 17 obese African-American and Caucasian adolescents receiving orlistat, 120 mg three times daily, McDuffie et al. ¹⁴⁵ observed several significant nutrient depletion patterns despite coadministration of a daily multivitamin supplement containing vitamin A (5000 IU), vitamin D (400 IU), vitamin E (300 IU), and vitamin K (25 µg). In particular, mean serum levels of vitamin D were significantly reduced compared with baseline after 1 month of orlistat, despite multivitamin supplementation.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Predictably, in view of its known pharmacological effects, orlistat interferes with absorption of fat-soluble nutrients, including vitamin D. The question of whether, and for which individuals, the probable decline in vitamin D blood level reaches a threshold of clinical significance remains unclear and worthy of further clinical trials. Pending conclusive research findings, physicians prescribing orlistat for 6 months or longer are advised to err on the side of prudence and coadminister supplemental vitamin D (and possibly vitamin A), potentially in the form of a moderate-dosage multivitamin combination. Separating intake of orlistat and supplemental nutrients by 2 or more hours may reduce adverse effects on absorption. Notably, the U.S. Food and Drug Administration (FDA) requires that food products containing olestra, which also inhibits fat absorption, include vitamin D and other fat-soluble vitamins (i.e., vitamins A, E, and K).

Raloxifene

Raloxifene (Evista).

Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Effect and Mechanism of Action

The ability of raloxifene, a selective estrogen receptor modifier (SERM) that is an analog of tamoxifen, to inhibit bone resorption and maintain or increase BMD depends on calcium nutriture and vitamin D's role in enabling calcium absorption and bone metabolism. Vitamin D can increase effectiveness of the drug.

Research

Boivin et al. ¹⁴⁶ found that the coadministration of calcium (500 mg) and vitamin D ³ (400-600 IU) with raloxifene increased the degree of mineralization of bone in postmenopausal women, as demonstrated by iliac crest biopsies. All currently approved bone-active pharmacological agents have been studied only in conjunction with supplemental calcium, and newer anabolic agents increase mineral demand in skeletal tissue and will thus require even higher levels of calcium repletion. ⁷⁸

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Calcium and vitamin D are essential for maintaining bone mass and density and imperative to the success of drug therapies for inducing bone augmentation. ⁷⁷ Deficiencies of both nutrients are common in the patient populations at highest risk for osteoporosis. The importance of exercise and sound nutrition (including adequate protein and phosphorus intake) as foundational cannot be overemphasized and is supported by growing evidence. Calcium has a clearly demonstrated effect of enhancing estrogen's effects on bone metabolism. Further, most research indicates that consistent exposure to sunlight provides a safe and effective, as well as otherwise beneficial, method of elevating vitamin D levels. Doses of 1500 mg calcium and 800 IU vitamin D daily provide prudent nutritional support for osteoporosis prevention and treatment.

In addition to these primary and secondary therapies, the use of raloxifene in postmenopausal women can provide a potent intervention in reversing bone loss and supporting healthy bone mass, although it does tend to increase, rather than decrease, menopausal symptoms. Raloxifene may also be useful in reducing the risk of breast cancer in this population.

Rifampin

Rifampin (Rifadin, Rifadin IV); combination drugs: isoniazid and rifampicin (Rifamate, Rimactane); isoniazid, pyrazinamide, and rifampicin (Rifater). See also Isoniazid section.

	Drug-Induced Nutrient Depletion, Coadministration Therapeutic, with Professional Management
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management

Probability: 2. Probable
Evidence Base:

Effect and Mechanism of Action

Pharmacokinetic interaction occurs because rifampin is a potent inducer of hepatic drug metabolism, specifically (cytochrome P450) 2C9, 2C19, and 3A4. Rifampin inhibits CYP1A2 and increases oxidation of antipyrine and 6β-hydroxycortisol, potentially causing decreased plasma levels of 25-hydroxycholecalciferol (25-OHD), which represents the body stores of active vitamin D precursor. ¹⁴⁷

Research

In a small study with eight male subjects, Brodie et al. ¹⁴⁷ found that a 2-week course of rifampicin (600 mg/day orally) produced a consistent fall in plasma 25-OHD levels of approximately 70%. Within the time frame of the study, plasma levels of 1,25-dihydroxycholecalciferol, PTH, and calcitonin were not significantly altered.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing rifampicin for extended periods would be prudent to coadminister supplemental vitamin D at a dosage level appropriate to the patient's age, weight, sun exposure, and other characteristics and needs. Regular monitoring of 25-OHD would be appropriate.

Thiazide Diuretics

Bendroflumethiazide (bendrofluazide; Naturetin); combination drug: bendrofluazide and propranolol (Inderex); benzthiazide (Exna), chlorothiazide (Diuril), chlorthalidone (Hygroton), cyclopenthiazide (Navidrex); combination drug: cyclopenthiazide and oxprenolol hydrochloride (Trasidrex); hydrochlorothiazide (Aquazide, Esidrix, Ezide, Hydrocot, HydroDiuril, Microzide, Oretic); combination drugs: hydrochlorothiazide and amiloride (Moduretic); hydrochlorothiazide and captopril (Acezide, Capto-Co, Captozide, Co-Zidocapt); hydrochlorothiazide and enalapril (Vaseretic); hydrochlorothiazide and lisinopril (Prinzide, Zestoretic); hydrochlorothiazide and losartan (Hyzaar); hydrochlorothiazide and metoprolol (Lopressor HCT); hydrochlorothiazide and spironolactone (Aldactazide); hydrochlorothiazide and triamterene (Dyazide, Maxzide), hydroflumethiazide (Diucardin), methyclothiazide (Enduron), metolazone (Zaroxolyn, Mykrox), polythiazide (Renese), quinethazone (Hydromox), trichlormethiazide (Naqua).

	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Minimal to Mild Adverse Interaction—Vigilance Necessary

Probability: 5. Improbable
Evidence Base:

Inadequate

Effect and Mechanism of Action

Thiazide diuretics induce changes in renal tubules that reduce calcium excretion and could potentially lead to hypercalcemia in rare instances and changes in vitamin D metabolism (particularly increases in serum levels of 24,25-dihydroxycholecalciferol).

Research

Riis and Christiansen ¹⁴⁸ studied the actions of bendroflumethiazide (5 mg/day), along with 500 mg/day calcium, on vitamin D metabolism in a 12-month, placebo-controlled clinical trial in 19 healthy, early-postmenopausal women. Subjects in the thiazide group demonstrated a significant elevation in the serum concentration of 24,25-dihydroxycholecalciferol and a tendency toward decreased serum 1,25-dihydroxycholecalciferol, although mean serum 25-hydroxycholecalciferol remained unchanged.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Given the uncertain implications of such findings, physicians are advised to closely supervise and regularly monitor serum calcium levels when prescribing thiazide diuretics. Special testing before initiating or increasing any vitamin D supplementation is probably unnecessary.

Thioridazine

Thioridazine (Mellaril).

Potentially Harmful or Serious Adverse Interaction—Avoid

Probability: 2. Probable
Evidence Base:

Verapamil and Related Calcium Channel Blockers

Effect and Mechanism of Action

Cholecalciferol (vitamin D ³ ), as a cytochrome P2D6 inhibitor, may decrease the metabolism of thioridazine via CYP isoenzymes.

Research

In a double-blind, randomized-order, crossover study of thioridazine pharmacodynamics, Hartigan-Go et al. ¹⁴⁹ used debrisoquin, an agent presumed to be extensively metabolized by CYP2D6, to determine the hydroxylation status of thioridazine. They also found that thioridazine can prolong QTc intervals in a dose-dependent manner in normal subjects. ¹⁴⁹ Furthermore, a manufacturer of thioridazine determined that the peak concentration (C ^max ) of thioridazine (single oral dose of 25 mg) is highly variable, and that some individuals are “slow hydroxylators” and others are “rapid hydroxylators.” In regard to the effects of CYP2D6 inhibition, compared with placebo, thioridazine increased QTc intervals by 9 msec and 23 msec with 10-mg and 50-mg doses, respectively. ¹⁵⁰

Clinical Implications and Adaptations

Concomitant use of thioridazine and agents that inhibit CYP2D6 isoenzymes such as cholecalciferol is contraindicated and should be avoided. Evidence is lacking to suggest that supplementation with forms of vitamin D other than cholecalciferol (vitamin D ³ ) is problematic, and vitamin D support is often important in patients being treated with thioridazine.

Alternatives to thioridazine may need to be considered when supplementation with vitamin D ³ is critical to a patient's medical needs and central to the therapeutic strategy for their comprehensive care. Regardless, an alternate drug choice may be necessary because this phenothiazine antipsychotic has been withdrawn from the market in many jurisdictions.

Evidence: Verapamil (Calan, Calan SR, Covera-HS, Isoptin, Isoptin SR, Verelan, Verelan PM). Extrapolated, based on similar properties: Amlodipine (Norvasc); combination drug: amlodipine and benazepril (Lotrel); bepridil (Bapadin, Vascor), diltiazem (Cardizem, Cardizem CD, Cardizem SR, Cartia XT, Dilacor XR, Diltia XT, Tiamate, Tiazac), felodipine (Plendil); combination drugs: felodipine and enalapril (Lexxel); felodipine and ramipril (Triapin); gallopamil (D600), isradipine (DynaCirc, DynaCirc CR), lercanidipine (Zanidip), nicardipine (Cardene, Cardene I.V., Cardene SR), nifedipine (Adalat, Adalat CC, Nifedical XL, Procardia, Procardia XL); combination drug: nifedipine and atenolol (Beta-Adalat, Tenif); nimodipine (Nimotop), nisoldipine (Sular), nitrendipine (Cardif, Nitrepin), verapamil combination drug: Verapamil and trandolapril (Tarka).

	Potentially Harmful or Serious Adverse Interaction—Avoid
	Impaired Drug Absorption and Bioavailability, Avoidance Recommended
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Probability: 5. Improbable
Evidence Base: